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The next generation of Treatment for Hepatitis C. Treatment of CHC: Outcomes. Goal of therapy is to render the patient PCR negative for HCV RNA Need to remain PCR negative 6 months after end of therapy Response rates for combination therapy Genotype 1 up to 40% Genotypes 2 or 3 up to 80%.

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Treatment of chc outcomes
Treatment of CHC: Outcomes

  • Goal of therapy is to render the patient PCR negative for HCV RNA

  • Need to remain PCR negative 6 months after end of therapy

  • Response rates for combination therapy

    • Genotype 1 up to 40%

    • Genotypes 2 or 3 up to 80%


Evolution of hcv genotype 1 treatment
Evolution of HCV genotype 1 treatment

100

80

  • 42–54%

Peg-IFN + RBV2–4

  • 16–28%

60

IFN + RBV1

SVR rate (%)

  • 2–7%

IFN1

40

20

1990

2000

2020

2010

  • IFN: interferon; RBV: ribavirin Peg-IFN: peginterferonDAA: direct-acting antiviralSVR: sustained virologic response

1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–823. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–555. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14


Treatment issues
Treatment Issues

  • Genotypes 2/3 – nothing new on horizon

  • Genotype 1 – failure rate 50-60%

  • No good options for treatment failures



Direct acting anivirals daas
Direct Acting Anivirals (DAAs)

  • DAA-based triple combination therapy led to improved SVR rates over current therapy in Phase II trials

    • 61–85% SVR with telaprevir-based therapy4–6

    • 54–75% SVR with boceprevir-based therapy7

  • Telaprevir and boceprevir have recently completed Phase III trials in treatment-naïve patients

    • Telaprevir: ADVANCE8 and ILLUMINATE9

    • Boceprevir: SPRINT-210


Advance telaprevir study design n 1088

Pbo +

PR

TVR

+

PR

PR

PR

PR

PR

Pbo + PR

TVR + PR

PR

ADVANCE (telaprevir): study design (N=1088)

PR48 (control)(N=361)

SVR

Follow-up

SVR

eRVR+

Follow-up

Follow-up

T12PR(N=363)

eRVR–

SVR

Follow-up

SVR

eRVR+

Follow-up

Follow-up

T8PR(N=364)

SVR

eRVR–

Follow-up

0

8

12

24

36

48

72

Weeks

Peg-IFN alfa-2a dose: 180 µg/week; RBV dose: 1000 or 1200 mg/dayeRVR: extended rapid virologic response (undetectable HCV RNA at Weeks 4 and 12); Pbo: placebo; PR: peginterferon/ribavirin; TVR: telaprevir

Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A


Sprint 2 boceprevir study design n 1097

SVR

SVR

SVR

SVR

PRlead-in

PRlead-in

PRlead-in

Follow-up

PR + Placebo

Follow-up

Follow-up

Follow-up

PR + Boceprevir

PR + Boceprevir

PR + Placebo

SPRINT-2 (boceprevir): study design (N=1097)

PR48 ControlN=363

Weeks 8–24 HCV RNA undetectable

BOC

RGT

N=368

Weeks 8–24 HCV RNA detectable*

BOC44/

PR48

N=366

24

28

0

4

8

48

72

Weeks

*But with undetectable HCV RNA at Week 24

Peg-IFN alfa-2b dose: 1.5 µg/kg/week

RBV dose: 600–1400 mg/day in a divided daily doseRGT: response-guided therapy

Poordad F, et al. Hepatology 2010;52(Suppl.):402A


Illuminate telaprevir study design n 540

eRVR+

T12PR48N=160

eRVR+

T12PR24

N=162

eRVR–

T12PR48

N=118

PR

PR

PR

T12PR

PR

ILLUMINATE (telaprevir): study design (N=540)

SVR

72 weeks

Follow-up

Follow-up

Non-inferiority (NI)

Randomized Treatments

eRVR+

SVR

Follow-up

Assigned Treatment

SVR

eRVR–

Follow-up

0 12 20

20 24 36 48 60 72

Weeks

Patients discontinued for any reason before Week 20 randomization were categorized as ‘Other’ (N=100)Stopping rules were similar to ADVANCE

Sherman KE, et al. Hepatology 2010;52(Suppl.):401A


Advance and illuminate svr rates with telaprevir based therapy versus pr alone
ADVANCE and ILLUMINATE: SVR rates with telaprevir-based therapy versus PR alone

72–75*

T12PR

659/903

PR48

158/361

Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A; Sherman KE, et al. CROI 2011. Abstract 957

*p<0.0001 vs PR48 in ADVANCE (75% versus 44%)


Sprint 2 svr rates with boceprevir based therapy versus pr alone
SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone

BOC44/PR48

242/366

PR48

137/363

BOC RGT

233/368

For non-Black patients, p<0.0001 for both boceprevir arms versus PR48; for Black patients, p=0.044 and p=0.004 for BOC RGT and BOC44/PR48, respectively, versus PR48

Adapted from Poordad F, et al. Hepatology 2010;52(Suppl.):402A


Tripple therapy works in advanced fibrosis advance telaprevir svr rates by fibrosis stage
Tripple therapy works in advanced fibrosis aloneADVANCE (telaprevir): SVR rates by fibrosis stage

ADVANCE1

No, minimal or portal fibrosis

Bridging fibrosis or cirrhosis

SVR (%)

PR48134/288

T12PR226/290

PR4824/73

T12PR45/73

n/N=

1. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A;


Tripple therapy works in all il28b genotypes advance telaprevir svr rates by il28b genotype
Tripple therapy works in all IL28B genotypes aloneADVANCE (telaprevir): SVR rates by IL28B genotype

CC

CT

TT

SVR (%)

PR4820/80

T12PR48/68

PR4835/55

T12PR45/50

PR486/26

T12PR16/22

n/N=

Samples were available for 454/1088 (42%) patients enrolled in ADVANCE

Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542


Safety and tolerability with daas
Safety and tolerability with DAAs alone

  • Common AEs with PR include:1–3

    • Fatigue, headache, nausea, pyrexia and myalgia

    • Anemia and neutropenia

    • Depression, irritability and insomnia

    • Rash

  • Additional management considerations with DAAs

    • Telaprevir:4–6 rash, anemia

    • Boceprevir:7,8 anemia and dysgeusia

1. Pegintron EMA Summary of Product Characteristics; 2. Pegasys EMA Summary of Product Characteristics3. Rebetol EMA Summary of Product Characteristics; 4. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

5. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A; 6. Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):147. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Bacon BR, et al. Hepatology 2010;52(Suppl.):430A

AE: adverse event


Evolution of hcv genotype 1 treatment1
Evolution of HCV genotype 1 treatment alone

100

  • 59–75%

DAA+Peg-IFN + RBV5–8

80

  • 42–54%

Peg-IFN + RBV2–4

  • 16–28%

60

IFN + RBV1

SVR rate (%)

  • 2–7%

IFN1

40

20

1990

2000

2020

2010

  • IFN: interferon; RBV: ribavirin Peg-IFN: peginterferonDAA: direct-acting antiviralSVR: sustained virologic response

1. McHutchison JG, et al. N Engl J Med 1998;339:1485–92; 2. Fried M, et al. N Engl J Med 2002;347:975–823. Manns MP, et al. Lancet 2001;358:958–65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346–555. Jacobson IM, et al. Hepatology 2010;52(Suppl):427A; 6. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A7. Poordad F, et al. Hepatology 2010;52(Suppl.):402A; 8. Foster GR, et al. Hepatol Int 2011;5(Suppl.1):14



Definitions of failure on prior peg ifn rbv therapy
Definitions of failure on prior Peg-IFN/RBV therapy failure?

Null response

Relapse

Non-response

2 log10 drop

HCV RNA level

Partial response

Detection limit

Treatment

Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22


Realize telaprevir svr in prior relapsers partial responders and null responders
REALIZE (telaprevir): SVR in prior relapsers, partial responders and null responders

Prior relapsers

Prior partialresponders

Prior null responders

*

*

*

*

SVR (%)

*

*

LI T12/PR4826/48

T12/PR4829/49

PR48

4/27

PR48

2/37

LI T12/PR4825/75

T12/PR4821/72

PR48

16/68

LI T12/PR48124/141

T12/PR48121/145

n/N=

*p<0.001 vs PR48; post-hoc analysis

Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14


Respond 2 boceprevir svr in prior relapsers and partial responders
RESPOND-2 (boceprevir): SVR in prior relapsers and partial responders

Prior relapsers

Prior partialresponders

Prior null responders were excluded from RESPOND-2

SVR (%)

BOCRGT

23/57

BOC44/PR4830/58

PR48

2/29

PR48

15/51

BOC RGT

72/105

BOC44/PR4877/103

n/N=

Bacon BR, et al. Hepatology 2010;52(Suppl.):430A


Summary of tripple therapy with daas
Summary of Tripple therapy with DAAs responders

  • Only for Genotype 1 Hepatitis C

  • Uses Peg Inf + Ribavirin + DDA

  • Improved response in naïve patients (65-75%)

  • Improved response in prior non-responders

  • Improved response in difficult to treat groups


COST responders

  • Cost of treatment

    • genotype 1 £12,782 for 48 weeks treatment

    • genotype 2 or 3 £5,233 for 24 weeks

  • Supportive therapy with:

    • Epoetin - 8000 units twice weekly = £3,216 for 6 months

    • G-CSF - Neupogen 30million units/wk = £1752 for 6 months

  • Cost of addition of DAA £14,000 - £24,000

    • To be confirmed Sept 2011



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